Noise-induced hearing loss (NIHL) is one of the most common causes of acquired hearing loss. Corresponding with its functional deficit, loss of outer hair cells (OHCs) is the primary inner ear pathology. Currently, a comprehensive mechanism of OHC death in NIHL remains unknown, and no established clinical therapy for the prevention and treatment of NIHL exists. This proposal aims to elucidate the molecular mechanisms of hair cell death in NIHL in order to better understand the mechanisms underlying NIHL and develop a comprehensive therapy. Our preliminary data have shown transient cellular energy depletion and increased active AMPK levels in sensory hair cells in response to traumatic noise, accompanied by decreased p-Akt levels in outer hair cells (OHCs). This proposal tests the hypothesis that noise trauma causes a transient cellular energy depletion that blocks Akt pro-survival signaling and activates pro-apoptotic JNK via LKB1-dependent AMPK activation, leading to hair cell death. CBA/J mice will be used to address the signaling pathways of AMPK activation that lead to OHC death. In Aim 1, energy depletion in noise-induced activation of AMPK in OHCs will be determined by exposing CBA/J mice to broadband noise. The cellular energy buffer phosphocreatine will be used to prevent noise-induced energy depletion. Additionally, the detailed mechanism of AMPK activation following noise exposure will be analyzed by utilizing LKB1 silencing techniques in vivo. In Aim 2, the role of AMPK in inhibiting Akt-mediated pro-survival and activating pro-apoptotic JNK in OHCs following noise exposure will be determined by exposing CBA/J mice to broadband noise. The cellular energy buffer phosphocreatine will be used to prevent noise-induced energy depletion and AMPK silencing techniques will be used to examine if AMPK blocks pro-survival signaling and activates pro-apoptotic signaling. We expect the outcome of this study will have a profound impact on understanding the basic molecular mechanism of hair cell loss in NIHL and shed light on the identification of new targets for the prevention of NIHL. In addition, this fellowship will train te applicant towards a successful research career.